Abstract:

The present invention is directed to novel pharmaceutically acceptable
polymeric compositions suitable for melt extrusion and injection moulding
of single or multi-component pharmaceutical dosage forms comprising a
plurality of drug substance containing sub-units, being capsule
compartments and/or solid sub-units comprising a solid matrix of a
polymer which contains a drug substance, the sub-units being connected
together in the assembled dosage form.

Claims:

1. A dosage form comprising at least one of:(a) a shell including a first
wall portion at least partially defining an interior space configured to
hold a drug substance, the first wall portion being configured to
dissolve within a gastrointestinal environment; or(b) a linker including
a second wall portion having a substantially cylindrical outer surface,
the second wall portion configured to dissolve within a gastrointestinal
environment;wherein a respective one of the first or second wall portions
are made from an extruded pharmaceutical composition comprising
hydroxypropylmethylcellulose acetate succinate (HPMC-AS) present in an
amount of about 20 to about 70% w/w; at least one plasticizer present in
an amount of about 1% to about 20% w/w; a lubricant present in an amount
of about 2% to about 10% w/w; and at least one dissolution modifying
excipient selected from the group consisting of a disintegrant present it
is in an amount of about 2% to about 20% w/w, a swellable solid present
it is in an amount of about 10 to about 60% w/w, and a wicking agent
present it is in an amount of about 2.5 to about 15% w/w, and a
combination or mixture thereof.

2. The dosage form according to claim 1 wherein the HPMC-AS is present in
an amount of about 55 to about 65% w/w.

4. The dosage form according to claim 3 wherein the lubricant is stearyl
alcohol.

5. The dosage form according to claim 4 wherein the stearyl alcohol is
present from about 4 to about 10% w/w.

6. The dosage form according to claim 1 wherein the at least one
dissolution modifying excipient is a swellable solid.

7. The dosage form according to claim 6 wherein the swellable solid is at
least one of hydroxypropyl cellulose, hydroxypropylmethyl cellulose, or
hydroxypropylmethyl cellulose phthalate, or a combination or mixture
thereof.

8. The dosage form according to claim 7 wherein the swellable solid is a
combination of hydroxypropyl cellulose and hydroxypropylmethyl cellulose.

9. The dosage form according to claim 7 wherein the swellable solid is a
combination of hydroxypropyl cellulose and hydroxypropylmethyl cellulose
phthalate.

10. The dosage form according to claim 6 wherein the swellable solid is a
blend of hydroxypropyl cellulose polymers each having differing molecular
weights.

11. The dosage form according to claim 10 wherein the blend of
hydroxypropyl cellulose polymers are present in a total amount of about
20% to about 50% w/w.

12. The dosage form according to claim 1 wherein the at least one
dissolution modifying agent is a wicking agent which is a low molecular
weight solute or a sugar selected from xylitol, mannitol, lactose,
starch, or sodium chloride, or combinations or mixtures thereof.

13. The dosage form according to claim 1 wherein the at least one
dissolution modifying excipient is a disintegrant.

14. The dosage form according to claim 13 wherein the disintegrant is
sodium starch glycollate, croscarmellose sodium, crospovidone
(cross-linked polyvinyl pyrrolidone), copovidone, polyvinyl pyrrolidone,
or a combination or mixture thereof.

15. The dosage form according to claim 13 wherein the at least one
dissolution modifying excipient is a disintegrant present in an amount of
about 5 to about 10% w/w.

17. The dosage form according to claim 16 wherein the plasticizer is
triacetin.

18. The dosage form according to claim 17 wherein the triacetin is present
in an in a ratio with HPMC-AS of about 1:4 to 1:7.

19. The dosage form according to claim 16 wherein the plasticizer is
triethyl citrate or glycerol.

20. The dosage form according to claim 16 wherein the plasticizer is a
mixture of glycerol and propylene glycol.

21. The dosage form according to claim 16 wherein the plasticizer is a
mixture of triethyl citrate and propylene glycol.

22. The dosage form according to claims 16 wherein the plasticizer is a
mixture of two or more plasticizers present in an amount of about 10% w/w
to about 20% w/w.

23. The dosage form according to claim 1 which further comprises a
surfactant present in an amount of 1 to about 10%, and/or a processing
agent present in an amount of about 1 to about 10% w/w.

24. The dosage form according to claim 1 wherein the lubricant is stearyl
alcohol, the dissolution modifying excipient is HPC or a blend of
differing molecular weights of HPC, and the plasticizer is TEC or
triacetin.

25. The dosage form according to claim 1 wherein the grade of HPMC-AS is
HPMC-AS LG.

26. The dosage form according to claim 1 wherein HPMC-AS is present in an
amount of about 50 to about 65% w/w, the dissolution modifying excipient
is HPMC phthalate present in an amount from about 10 to about 50% w/w,
the lubricant is stearyl alcohol present in an amount of about 4 to about
10% w/w, and at least one plasticizer present in an amount of about 10 to
about 20% w/w.

27. The dosage form according to claim 26 wherein the plasticizer is
glycerol or propylene glycol, or a combination or mixture thereof.

28. The dosage form according to claim 26 wherein the plasticizer is TEC
or propylene glycol, or a combination or mixture thereof.

29. The dosage form according to claim 1 wherein the at least one
dissolution modifying excipient is a swellable solid which is HPC and a
second swellable solid which is HPMC, present in the formulation in an
amount of about 2 to about 10% w/w.

31. The dosage form according to claim 26 wherein the HPMC-AS is LG grade.

32. The dosage form according to claim 1 wherein the lubricant is stearyl
alcohol and is present in an amount of from about 3.75 to about 6.25%
w/w.

33. The dosage form according to claim 30 wherein the HPMC-AS,
hypromellose phthalate, hydroxypropylcellulose, propylene glycol,
glycerol, and stearyl alcohol are present in the formulation as
58.5/18.5/3/10/5/5% w/w.

35. The dosage form according to claim 1 wherein HPMC-AS is present in an
amount of about 50 to about 65% w/w.

36. The dosage form according to claim 1 wherein HPMC-AS is present in an
amount of about 40 to about 70% w/w.

37. A dosage form comprising at least one of:(a) a shell including a first
wall portion at least partially defining an interior space configured to
hold a drug substance, the first wall portion being configured to
dissolve within a gastrointestinal environment; or(b) a linker including
a second wall portion having a substantially cylindrical outer surface,
the second wall portion configured to dissolve within a gastrointestinal
environment;wherein a respective one of the first or second wall portions
are made from an extruded pharmaceutical composition comprising
hydroxypropylmethylcellulose acetate succinate (HPMC-AS) present in an
amount of about 40 to 70% w/w, stearyl alcohol present in an amount of
about 5 to about 10% w/w; a hydroxypropylcellulose derivative present in
an amount of about 10 to about 50% w/w; and at least one plasticizer
present in an amount of about 1 to about 30% w/w.

38. The dosage form according to claim 37 wherein the hydroxypropyl
cellulose has a molecular weight of <130,000.

39. The dosage form according to claim 37 wherein the plasticizer is
triacetin.

40. The dosage form according to claims 37 wherein the HPMC-AS is LG
grade.

42. A multicomponent dosage form comprising a plurality of sub-units, and
wherein each sub-unit being selected from(a) at least one shell including
a first wall portion at least partially defining an interior space
configured to hold a drug substance, the first wall portion being
configured to dissolve within a gastrointestinal environment; and(b) at
least one linker including a second wall portion having a substantially
cylindrical outer surface, the second wall portion configured to dissolve
within a gastrointestinal environment;and wherein the drug substance
containing capsule has a shell wall comprising
hydroxypropylmethylcellulose acetate succinate (HPMC-AS) present in an
amount of about 20 to 70% w/w, at least one plasticizer present in an
amount of about 1% to about 20% w/w, a lubricant present in an amount of
about 2% to about 15% w/w, and a swellable solid present in an amount of
about 10 to about 60% w/w, and containing a drug substance;which, at
least prior to administration to a patient, is mechanically welded or
mechanically joined into an assembled dosage form.

43. The multicomponent dosage form according to claim 42 wherein the at
least one linker is composed of ethylcellulose, stearyl alcohol,
glycerol, and BHT (butylated hydroxytoluene).

44. The multicomponent dosage form according to claim 42 wherein the at
least one linker is composed of Eudragit RL100, hydroxypropylcellulose
and stearyl alcohol.

45. The multicomponent dosage form according to claim 42, in which the at
least one drug substance-containing capsule compartment has a wall with a
thickness in the range of about 0.1-0.8 mm.

46. The multicomponent dosage form according to claim 42, in which the at
least one drug substance-containing capsule compartment is a
substantially sustained release.

47. The multicomponent dosage form according to claim 42 which further
comprises a second drug substance-containing capsule compartment which is
of substantially immediate release.

Description:

[0002]This invention relates to the preparation of injection molded single
or multi-component dosage forms using novel pharmaceutically acceptable
polymeric blends.

BACKGROUND OF THE INVENTION

[0003]Various types of pharmaceutical dosage forms are known for oral
dosing. Pharmaceutical capsules are well known, generally being intended
for oral dosing. Such capsules generally comprise an envelope wall of a
pharmaceutically acceptable, e.g. orally ingestible, polymer material
such as gelatin, although other materials for capsule walls, e.g. starch
and cellulose based polymers are also known. Such capsules generally have
soft walls made by making a film on a capsule former, which is then
allowed to dry. Rigid walled capsules made by injection molding are also
known, see for example U.S. Pat. No. 4,576,284; U.S. Pat. No. 4,591,475;
U.S. Pat. No. 4,655,840; U.S. Pat. No. 4,738,724; U.S. Pat. No. 4,738,817
and U.S. Pat. No. 4,790,881 (all to Warner Lambert). These disclose
specific constructions of capsules made of gelatin, starch and other
polymers, and methods of making them by injection molding of hydrophilic
polymer--water mixtures. U.S. Pat. No. 4,576,284 specifically discloses
such capsules provided with a cap which closes the capsule, and which is
formed in situ on the filled capsule by molding. U.S. Pat. No. 4,738,724
discloses a wide range of rigid capsule shapes and parts.

[0004]Multi-compartment capsules, including those of the type where each
compartment has different drug release characteristics, or for example,
contains a different drug substance or formulation are also known, for
example in U.S. Pat. No. 4,738,724 (Warner-Lambert); U.S. Pat. No.
5,672,359 (University of Kentucky); U.S. Pat. No. 5,443,461 (Alza Corp.);
WO 95/16438 (Cortecs Ltd.); WO 90/12567 (Helminthology Inst.);
DE-A-3727894, and BE 900950 (Warner Lambert); FR 2524311, and NL 7610038
(Tapanhony Nev.); FR 1,454,013 (Pluripharm); U.S. Pat. No. 3,228,789
(Glassman); and U.S. Pat. No. 3,186,910 (Glassman) among others. U.S.
Pat. No. 4,738,817 discloses a multicompartment capsule with a similar
construction to those of U.S. Pat. No. 3,228,789 and U.S. Pat. No.
3,186,910 made of a water-plasticized gelatin. U.S. Pat. No. 4,738,817
('817) Witter et al., U.S. Pat. No. 4,790, 881 ('881) Wittwer et al., and
EP 0 092 908, Wittwer, F., all discloses injection molded capsules
prepared with gelatin and other excipients. Wittwer et al. '817 and '881
also prepare capsules with other hydrophilic polymers, such as
hydroxypropylmethyl-cellulose phthalate (HPMCP), methylcellulose,
microcrystalline cellulose, polyethylene glycol, cellulose acetate
phthalate (CAP) and with polyvinylpyrrolidone. Both U.S. Pat. No.
4,790,881 and EP 0 091 908 propose other polymers having enteric
properties suitable for use, including generally acrylates and
methacrylates (Eudragits) although none are demonstrated and no specific
details are provided.

[0005]Pharmaceutical dosage forms are also known which comprise a matrix
of a solid polymer in which a drug substance is dispersed, embedded or
dissolved as a solid solution. Such matrixes may be formed by an
injection molding process. This technology is discussed in Cuff G, and
Raouf F, Pharmaceutical Technology, June (1998) pages 96-106. Some
specific formulations for such dosage forms are disclosed in U.S. Pat.
No. 4,678,516; U.S. Pat. No. 4,806,337; U.S. Pat. No. 4,764,378; U.S.
Pat. No. 5,004,601; U.S. Pat. No. 5,135,752; U.S. Pat. No. 5,244,668;
U.S. Pat. No. 5,139,790; U.S. Pat. No. 5,082,655; U.S. Pat. No.
5,552,159; U.S. Pat. No. 5,939,099; U.S. Pat. No. 5,741,519; U.S. Pat.
No. 4,801,460; U.S. Pat. No. 6,063,821; WO 99/27909; CA 2,227,272; CA
2,188,185; CA 2,211,671; CA 2,311,308; CA 2,298,659; CA 2,264,287; CA
2,253,695; CA 2,253,700; and CA 2,257,547 among others.

[0006]U.S. Pat. No. 5,705,189 is directed to a group of co-polymers of
methacrylic acid, methyl methacrylate and methyl acrylate, for use as
thermoplastic agents in the production of drugs coatings, and capsules.
No information is presented on the quality of the capsule formation with
respect to warping or other distortions produced by the injection molding
process. Nor is shear rate data presented for the viscosity/temperature
figures of the emulsions presented therein.

[0007]It would be desirable to prepare a pharmaceutical dosage form in
which a pharmaceutically acceptable polymeric blend is extruded by hot
melt into a suitable dosage form, or is injection molded into suitable
dosage forms which may be multicompartmental, such as in a capsule. This
pharmaceutical polymeric composition as the dosage form may provide
differing physio-chemical characteristics for each segment containing an
active agent, such that a convenient dosage form can be optioned which
may include a rapid dissolve, immediate, delayed, pulsatile or modified
release, and be produced by simply selecting the appropriate polymer(s)
to be molded for each section.

[0011]FIG. 4 demonstrates the dissolution profile for Metformin in a USP
III Dissolution with shells of HPMC-AS/HP-50/SSL/Propylene
Glycol/Glycerol/Stearyl Alcohol with an RL100 linker, run at 10 dpm in
0.1N HCl for 2 hours then pH 6.8 buffer.

[0014]The present invention is directed to a novel pharmaceutical
composition for making moulded articles, such as capsule shells, solid
sub-units, closures or linker sub-units comprising
hydroxypropylmethylcellulose acetate succinate (HPMC-AS) present in an
amount of about 20 to about 70% w/w; a plasticizer present in an amount
of about 1% to about 20% w/w; a lubricant present in an amount of about
2% to about 10% w/w; at least one dissolution modifying excipient
selected from a disintegrant, a swellable solid, or a wicking agent, or a
combination or mixture thereof, and wherein if the disintegrant is
present it is in an amount of about 2% to about 20% w/w, and wherein if
the swellable solid is present it is in an amount of about 10 to about
60% w/w, and wherein if a wicking agent is present it is in an amount of
about 2.5 to about 15% w/w.

[0015]The present invention is also directed to the process of making the
capsule shells, solid sub-units, closures or linker sub-units composed of
the above formulation, and multi-component dosage forms composed of these
assembled subunits, or other subunits of suitable formulations thereof.

DETAILED DESCRIPTION OF THE INVENTION

[0016]In one embodiment the present invention is direct to a dosage form
comprising at least one of:

(a) a shell including a first wall portion at least partially defining an
interior space configured to hold a drug substance, the first wall
portion being configured to dissolve within a gastrointestinal
environment; or(b) a linker including a second wall portion having a
substantially cylindrical outer surface, the second wall portion
configured to dissolve within a gastrointestinal environment;

[0017]wherein a respective one of the first or second wall portions are
made from an extruded pharmaceutical composition comprising
hydroxypropylmethylcellulose acetate succinate (HPMC-AS) present in an
amount of about 20 to about 70% w/w; at least one plasticizer present in
an amount of about 1% to about 20% w/w; a lubricant present in an amount
of about 2% to about 10% w/w; and at least one dissolution modifying
excipient selected from the group consisting of a disintegrant present it
is in an amount of about 2% to about 20% w/w, a swellable solid present
it is in an amount of about 10 to about 60% w/w, and a wicking agent
present it is in an amount of about 2.5 to about 15% w/w, and a
combination or mixture thereof.

[0018]In another embodiment the present invention is directed to a capsule
comprising a shell having an outer surface and an opposed inner surface,
the inner surface defining at least in part a confined space for holding
a drug substance, or a generally cylindrical linker body having an outer
surface, the shell or the linker being composed of an extruded material
comprising a pharmaceutical composition comprising
hydroxypropylmethylcellulose acetate succinate (HPMC-AS) present in an
amount of about 20 to about 70% w/w; at least one plasticizer present in
an amount of about 1% to about 15% w/w; a lubricant present in an amount
of about 2% to about 10% w/w; and at least one dissolution modifying
excipient selected from the group consisting of a disintegrant present it
is in an amount of about 2% to about 20% w/w, a swellable solid present
it is in an amount of about 10 to about 60% w/w, and a wicking agent
present it is in an amount of about 2.5 to about 15% w/w, and a
combination or mixture thereof.

[0019]Another embodiment of the invention is a dosage form component
configured as a hollow capsule, an end cap, or a linker, said component
consisting essentially of an extruded or injection moulded pharmaceutical
composition comprising hydroxypropylmethylcellulose acetate succinate
(HPMC-AS) present in an amount of about 20 to about 70% w/w; at least one
plasticizer present in an amount of about 1% to about 20% w/w; a
lubricant present in an amount of about 2% to about 10% w/w; and at least
one dissolution modifying excipient selected from the group consisting of
a disintegrant present it is in an amount of about 2% to about 20% w/w, a
swellable solid present it is in an amount of about 10 to about 60% w/w,
and a wicking agent present it is in an amount of about 2.5 to about 15%
w/w, and a combination or mixture thereof.

[0020]Another embodiment of the invention is a dosage form, comprising:

[0021]a) a capsule shell including a wall at least partially defining an
interior space for retaining a drug substance and being configured to
dissolve within a gastrointestinal environment; and

[0022]b) a linker including a wall having a substantially cylindrical
outer surface and being configured to dissolve within a gastrointestinal
environment;

[0023]wherein at least one of the capsule shell or the linker is made from
an extruded material comprising hydroxypropylmethylcellulose acetate
succinate (HPMC-AS) present in an amount of about 20 to about 70% w/w; at
least one plasticizer present in an amount of about 1% to about 20% w/w;
a lubricant present in an amount of about 2 % to about 10% w/w; and at
least one dissolution modifying excipient selected from the group
consisting of a disintegrant present it is in an amount of about 2% to
about 20% w/w, a swellable solid present it is in an amount of about 10
to about 60% w/w, and a wicking agent present it is in an amount of about
2.5 to about 15% w/w, and a combination or mixture thereof.

[0024]Therefore, one embodiment of the invention is a dosage form
comprising at least one of:

(a) a shell including a first wall portion at least partially defining an
interior space configured to hold a drug substance, the first wall
portion being configured to dissolve within a gastrointestinal
environment; or(b) a linker including a second wall portion having a
substantially cylindrical outer surface, the second wall portion
configured to dissolve within a gastrointestinal environment;

[0025]wherein a respective one of the first or second wall portions are
made from an extruded material comprising hydroxypropylmethylcellulose
acetate succinate (HPMC-AS) present in an amount of about 20 to about 70%
w/w; at least one plasticizer present in an amount of about 1% to about
20% w/w; a lubricant present in an amount of about 2% to about 10% w/w;
and at least one dissolution modifying excipient selected from the group
consisting of a disintegrant present it is in an amount of about 2% to
about 20% w/w, a swellable solid present it is in an amount of about 10
to about 60% w/w, and a wicking agent present it is in an amount of about
2.5 to about 15% w/w, and a combination or mixture thereof.

[0026]Another embodiment of the invention is a dosage form apparatus
comprising a wall portion configured to be dissolvable within a
gastrointestinal environment, the wall portion made from an extruded
material comprising hydroxypropylmethylcellulose acetate succinate
(HPMC-AS) present in an amount of about 20 to about 70% w/w; at least one
plasticizer present in an amount of about 1% to about 20% w/w; a
lubricant present in an amount of about 2% to about 10% w/w; and at least
one dissolution modifying excipient selected from the group consisting of
a disintegrant present it is in an amount of about 2% to about 20% w/w, a
swellable solid present it is in an amount of about 10 to about 60% w/w,
and a wicking agent present it is in an amount of about 2.5 to about 15%
w/w, and a combination or mixture thereof.

[0027]Another embodiment of the invention is a dosage form comprising at
least one subcomponent having a wall portion made from an extruded
material comprising hydroxypropylmethylcellulose acetate succinate
(HPMC-AS) present in an amount of about 20 to about 70% w/w; at least one
plasticizer present in an amount of about 1% to about 20% w/w; a
lubricant present in an amount of about 2% to about 10% w/w; and at least
one dissolution modifying excipient selected from the group consisting of
a disintegrant present it is in an amount of about 2% to about 20% w/w, a
swellable solid present it is in an amount of about 10 to about 60% w/w,
and a wicking agent present it is in an amount of about 2.5 to about 15%
w/w, and a combination or mixture thereof.

[0028]The present invention provides for novel pharmaceutical
compositions, and their use in melt extrusion technologies, and in the
making of injection molded articles, such as capsule shells, linkers,
spacers, and multicomponent injection molded capsule shells, linkers or
spacers, multicomponent pharmaceutical dosage forms, and other aspects as
defined in the claims and description of this application.

[0029]Another embodiment of the invention is to provide an alternative and
improved pharmaceutical dosage form which provides, inter alia, greater
flexibility in the dosage form adapted to a patient's specific
administration requirement, using the novel formulations of
pharmaceutically acceptable polymers and suitable excipients in said
dosage forms.

[0030]Another embodiment of the invention is to provide a process of
producing the multicomponent dosage forms comprising the novel
pharmaceutically acceptable polymeric blends by injection molding. These
multi-component dosage forms are suitable for containing a
pharmaceutically acceptable active agent, or agents, for release thereby.

[0031]In accordance with the invention, a melt extrusion composition, and
an injection molded capsule shell, and/or linker is provided for, with a
composition of hydroxypropyl methylcellulose acetate succinate (HPMC-AS)
and additional excipients.

[0032]In one embodiment of the invention, the capsule or linker subunits
comprises hydroxypropyl methylcellulose acetate succinate present in an
amount of about 10 to about 80% w/w, in combination with various other
excipients to product a formulation that can be first extruded, and if
desired injection moulded. The composition further comprises a
dissolution-modifying excipient (DME) present in an amount of 2.5% w/w to
about 60% w/w as determined by classification of DME; and a lubricant
present in an amount of about 1 to about 10% w/w, suitably from about 2
to about 10 w/w; and optionally a plasticizer present in an amount from
about 1% to about 15% w/w, and optionally a processing agent present in
an amount from about 1% to about 10% w/w.

[0033]In an alternative embodiment, the HPMC-AS is present in an amount of
about 20 to 70% w/w, alternatively from about 40 to about 70% w/w, and
alternatively in an amount of about 55 to about 65% w/w, and
alternatively in an amount about 60% w/w.

[0034]One embodiment of the present invention is the use of these
injection moulded parts which are resistant to gastric fluids, but deform
and dissolve in the higher pH of intestinal fluid and therefore provide a
mechanism for release of the contents of the these injection moulded,
orally dosed, capsules in the intestine.

[0035]In an alternative embodiment, the pharmaceutical dosage form
comprises a plurality of sub-units, each being a drug
substance-containing capsule compartment. In this case, each compartment
is physically separated from at least one adjacent compartment,
preferably by a wall made of a pharmaceutically acceptable polymer
material. In the case in which at least one of the sub-units is a drug
substance-containing capsule compartment its wall thickness is in the
range of about 0.1-0.8 mm. In another embodiment the wall thickness is in
the range of about 0.3-0.8 mm. In another embodiment the wall thickness
is in the range of about 0.3-0.5 mm.

[0036]The multi-component dosage form of the invention affords a high
degree of versatility in that it can be composed of various combinations
of different dosage forms having different release characteristics. For
example, the sub-units can be a substantially immediate release sub-unit,
a sustained release sub-unit, or a pulsed release sub-unit.

[0037]Other objects and advantages of the invention will be apparent from
the following description.

[0038]The present invention is directed to novel compositions of a
pharmaceutically acceptable polymer, hydroxypropyl methylcellulose
acetate succinate (HPMC AS) and pharmaceutically acceptable excipients,
which polymeric composition may be injection molded into one or more
components which can optionally be utilized together, such as in a
stacked or multi-component dosage form. It is recognized that the
polymeric blends may be injection molded into a single component that may
also contain the active agent for oral administration in the moulded
component, or the moulded component(s) may contain the active agent
within its cavities.

[0039]The present invention also relates to the application of a
pharmaceutically acceptable film coating over a component comprising the
novel pharmaceutically acceptable polymeric blends as described herein.
The film coating may be a delayed release coating, or a pH control
coating as are well known in the art. Such suitable coatings include but
are not limited to HPMC coatings, such as Opadry, and Eudragit coatings,
such as L30D-55. Enteric coatings, represented by application of L30D-55
for instance, may be applied using standard equipment such as a GMP
Aerocoater column coater. The component weight gain is nominally from
about 3% to about 5% w/w.

[0040]A desired attribute of the pharmaceutically acceptable polymeric
blends herein is to provide a consistent dissolution profile in vitro and
optimally in vivo.

[0041]A suitable multicomponent dosage form is disclosed in WO 01/08666,
and other related applications on structural features, or associated film
coatings, etc. for use with components or subunits of the above noted
formulations may be found in WO 01/08666; WO 04/010978, PCT/EP08/63852
(Attorney Docket No. PU62554), PCT/EP08/63853(Attorney Docket No.
PU62555), PCT/EP08/63856 (Attorney Docket No. PU62556), and
PCT/EP08/63857 (Attorney Docket No. PU62557) all filed 15 Oct. 2008.

[0042]Suitable formulations which may be used to derive parts of a dosage
form which may be used with part of a dosage form of this invention, e.g.
a capsule compartment wall, a solid sub-unit, or a closure or linker
sub-unit are disclosed in WO 02/060385, WO 02/060384, WO 05/089726, WO
05/009380, and U.S. Ser. No. 61/061275 filed 13 Jun. 2008 (Attorney
Docket No. PU62992P).

[0043]The parts of the dosage form of this invention, e.g. a capsule
compartment wall, a solid sub-unit, or a closure or linker sub-unit,
comprise a pharmaceutically acceptable polymeric blend (and adhesive
material if adhesive welds are formed) which is generally regarded as
safe, e.g. for oral ingestion and is capable of being formed into the
required shape of a capsule compartment wall, a solid sub-unit, or a
closure or linker as described above. A preferred method of forming the
polymer material into the desired shape is injection molding, which may
be a hot or cold runner injection molding process. Suitable injection
molding machines for such a process are known.

[0044]The pharmaceutical dosage form may comprise a plurality of capsule
compartments each bounded and physically separated from at least one
adjacent compartment by a wall made of a pharmaceutically acceptable
polymer material, such as described herein, adjacent compartments being
connected together in the assembled dosage form, and being retained
together by the connection at least prior to administration to a patient,
one or more of the compartments containing a drug substance. Suitably, in
the assembled dosage form of this first embodiment there are at least
two, for example three, such capsule compartments. Three or more such
compartments may be linearly disposed in the assembled dosage form, e.g.
in an arrangement comprising two end compartments at opposite ends of the
line, and one or more intermediate compartments. Suitably, there may be
two such capsule compartments. Suitably, one of such two capsule
compartments may be made of a material which is a sustained release
component, i.e. so that the capsule compartment wall dissolves, bursts or
is otherwise breached to release its contents after a delay, e.g. when
the compartment has reached the intestine. Suitably, the other of such
two capsule compartments may be made of a material which is an immediate
release component, i.e. so that the capsule compartment wall dissolves,
bursts or is otherwise breached to release its contents immediately or
effectively immediately, e.g. when the compartment is in the mouth or
stomach.

[0045]One or more, e.g. all, of the capsule compartments may for example
be substantially cylindrical, which term includes shapes which have a
circular, oval or oblate circular cross section across the longitudinal
axis, and shapes which have parallel or tapering e.g. with side walls
which taper conically over at least part of their extent. Such
substantially cylindrical capsule compartments may be provided with
connectable parts at one or both of their longitudinally disposed ends so
that the assembled dosage form may also be overall of a substantially
cylindrical shape.

[0047]Acrylic and/or methacrylic acid-based polymers which are soluble in
intestinal fluids and which can be formed into capsules are for example
disclosed in U.S. Pat. No. 5,705,189 (Roehm GmbH) which is incorporated
herein by reference. These poly(meth)acrylate copolymers were extrudable
and injection molded into capsule half s wherein the ratio of acrylic
and/or methacrylic acid was generally 20% w/w or more of the copolymer
(Examples 1-8). In these Examples, glycerol monostearate was added on a
16% w/w basis of the polymer as the sole mold-releasing agent.

[0048]In one embodiment of the invention herein, in order to produce
injection molded, non-distorted, unwarped capsule/sub-unit components for
assembly into either single capsule or multicompartment dosage forms
using HPMC-AS, at least one lubricant and a dissolution modifying agent
are included in the formulation as being useful to obtain release from
the injection molds.

[0049]HPMC-AS is the base polymer in the formulations described herein
that provides an enteric-like functionality to the injection moulded
parts. HPMC-AS is available in granular and in a fine micronised form in
three grades from Shin-Etsu Chemical Co. Ltd as Aquoat® AS-LG/LF,
Aquoat® AS-MG/MF and Aquoat® AS-HG/HF. The different grades are
defined by the number acetyl and succinoyl groups that are introduced to
the hydroxyl groups on the backbone of the polymer. L grades have an
acetyl content of 5.0%-9.0% and a succinoyl content of 14.0%-18.0%. M
grades have an acetyl content of 7.0%-11.0% and a succinoyl content of
10.0% -14.0%. H grades have an acetyl content of 10.0%-14.0% and a
succinoyl content of 4.0%-8.0%. All three of these grades are
demonstrated in the working examples herein.

[0050]It is recognized that HPMC-AS may be blended with other
pharmaceutically acceptable polymers, such as those described in detail
in the Handbook of Pharmaceutical excipients, published jointly by the
American Pharmaceutical association and the Pharmaceutical society of
Britain.

[0051]A number of different excipients were evaluated for use in with
HPMC-AS to create an enteric shell having favourable dissolution
profiles, physical stability, chemical stability, tensile strength and
ease and reproducibility of manufacture.

[0052]The HPMC-AS polymer is blended with additional excipients which
include, but are not limited to, lubricants, such as stearyl alcohol;
swelling agents, such as hydroxypropylcellulose, etc.; surfactants, such
as SDS or the Pluronic group of agents; pore-forming/channelling agents,
such as lactose or PEG; and additional buffering agents for adjust of
microclimate pH conditions.

[0053]Dissolution modifying agents, or substances are those that assist in
release modification, alter the erosion and/or swelling characteristics
of the capsule shell/linker/component. Many different classes of agents
may be used, such as the known super-disintegrants represented by sodium
starch glycollate, Ph. Eur. or sodium carboxymethyl starch, JPE
("Explotab"®, produced by JRS Products), croscarmellose sodium NF
(Aci-Di-Sol® produced by FMC), cross-linked PVP ("Kollidon-CL"), and
copovidone ("Kollidon VA 64"), both commercially available from BASF,
Starch 1500, and swelling agents such as polyvinyl pyrrolidone (PVP, also
know as POVIDONE, USP), manufactured by ISP-Plasdone or BASF-Kollidon,
primarily Grades with lower K values (K-15, K-25, but also K-30 to K-90);
and crospovidone (cross-linked polyvinyl pyrrolidone); and combinations
or mixtures thereof. Kollidan VA 64, or copovidone, is also known as
copolyvidone, copovidonum, copovidone or copovidon and is a ratio of two
monomers, vinylpyrrolidone and vinyl acetate.

[0054]Suitably, this class of disintegrants are present in the range of
about 2 to 20%, alternatively from about 5 to 10% w/w.

[0055]Another class of agents of dissolution modification agents for use
herein are the swellable solids, and include but are not limited to
poly(ethylene)oxide; the cellulosic derivatives, such as cellulose
acetate phthalate; hydroxypropylcellulose (HPC), such as the lower
molecular weights, e.g., KLUCEL EF and LF grades, and mixtures of the
lower molecular weights with higher molecular weight grades such as JF or
GF or alternative suppliers of HPC such as Nippon Soda Company, or Nisso
HPC, having a grade HPC-SSL; hydroxypropylmethyl cellulose (HPMC), and
hydroxypropylmethylcellulose phthalate (HPMCP), and other
hydroxyalkylcellulose derivatives. At least one commercial source of
hydroxypropylmethylcellulose phthalate is available from Shinetsu, Japan.

[0056]One source of HPC is marketed by Aqualon, a division of Hercules
Incorporated, as Klucel®. Klucel HPC is produced in various grades,
as determined by their intended use. Suitable Klucel polymers are Klucel
EF, Klucel JH, Klucel LF, and Klucel GF. Klucel E has a viscosity in the
range of 150-700 (a 300-600 mPas for EF pharm/EXF Pharm), and a molecular
weight of about 80,000; J has a viscosity of 150-400 and a molecular
weight of about 140,000, L has a viscosity in the range of 75-150, and a
molecular weight of about 95,000; and G has a viscosity in the range of
75-400, and a molecular weight of about 370,000.

[0057]One commercially available HPMC is Pharmacoat® 603.
Pharmacoat® is Hypromellose USP, produced by Shines, Chemical Company.
Hypromellose is also referred to as hydroxypropylmethylcellulose, and for
purposes herein used interchangeably. Pharmacoat 603 has a substitution
type of 2910 USP designation, and a labeled viscosity (cP or mpa's) of
2.4 to 3.6, a moisture permeability of 207, a methoxyl content of 28.0 to
30.0%, and a hydroxypropoxyl content of 7.0-12.0% (USP). An alternative
source of commercially available hypromellose having similar viscosity,
and substitution is Opadry® from Colorcon, N.J., USA, or Methocels
from Dow Chemical Company, Midland, Mich.

[0058]Suitably, these swellable solids are present in the range of about
10% to about 60% w/w. In another embodiment the swelling agent is present
in an amount from about 20 to about 30% w/w, or alternatively from about
10 to about 50% w/w. It is recognized that more than one swellable solid
may be used in combination in the formulations of this invention.

[0059]Therefore, one embodiment of the invention is a co-blend of HPMC-AS
with the polymer hydroxypropyl cellulose (HPC). In one embodiment of the
invention the coblend of HPMC-AS is with a swellable solid that is a
blend of at least two hydroxypropylcellulose derivatives each having
differing molecular weights.

[0060]One embodiment of the invention is a co-blend of HPMC-AS with the
polymer HPC having a viscosity in the range of 150-700, such as Klucel
EF. Suitably when Klucel EF is used as a DME it is in the range of 10 to
47.5% w/w.

[0061]Addition of these thermoplastic polymers to the blend is believed to
provide for improved tensile properties over HPMC-AS alone both pre and
post hydration, and enables swelling of the polymer at a pH of 1 to 6.

[0062]The co-blended polymers of HPC and HPMC-AS produce shells which
hydrate more than the non-blended polymeric composition (HPMC-AS alone)
under gastric conditions. This produces a formulation which has
significant improvements in dissolution reproducibility; an enhanced
hydration profile which results in less structural integrity, in alkaline
media, upon dissolution; and appearance and tensile properties of the
resulting shells.

[0063]Another embodiment of the invention is a co-blend of HPMC-AS with
the swellable solid hypromellose phthalate (HPMC-P or HPMCP) such as that
marketed by Shin Estu, as HP-50, HP-55, HP-55S®. Hypromellose
phthalate NF is also referred to as hydoxypropylmethylcellulose Phthalate
JP and is used interchangeably herewith. The viscosity of the HP-55 is 40
cSt, with a Nominal Phthalyl content 31%, a mean particle size (μm) of
1000 and dissolves in pH> or = to 5.5. HP55S is similar but for a
viscosity of 170 cST. The HP-50 is 55 cSt, with a Nominal Phthalyl
content 24%, a mean particle size (μm) of 1000 and dissolves in pH>
or = to 5.0.

[0064]Suitably if HPMCP is present in it is in the range of 10 to about
50% w/w, suitably from 15 to 30%, and in another embodiment it is present
in an amount of about 20 to 25% w/w. In one embodiment the HPMCP is HP50.

[0065]HP-50 has the lowest molecular weight and hence the lowest
viscosity. This was demonstrated to make processing easier, and HP-50
also contains the least amount of phthalic acid groups, perhaps providing
lower long term chemical instability.

[0066]HP-55 also dissolves at the higher pH (5.5 versus 5.0 for HP-50)
which could result in a longer release time in vivo if the pH rise is not
sufficient. HP-55S is the highest viscosity grade of HP-55, and hence
causes a bigger increase in torque and pressure on manufacture, which may
lead shells having higher levels of degradation. In general, shells
containing HP-50 appear to be more stable than either HP-55 or 55S and
dissolve faster.

[0067]In another embodiment of the invention the combination is suitably
HPMC-AS LG in combination with HPMC-phthalate (HPMCP) for formulation of
the capsule shell wall. In another embodiment the HPMC-AS is present in
an amount of about 50 to about 65% w/w, and an optimal ratio of
HPMC-AS:HPMCP is around 3:1.

[0068]Suitably, one formulation of the invention is HPMC-AS present in an
amount of about 50 to about 65% w/w, HPMCP is present in an amount from
about 15 to about 30% w/w. In another embodiment, HPMC-AS present in an
amount of about 50 to about 65% w/w, HPMCP is present in an amount from
about 15 to about 30% w/w, stearyl alcohol present in an amount of about
4 to about 10% w/w, and at least one plasticizer is present in an amount
of about 10 to about 20% w/w. In one embodiment the plasticizer is
selected from glycerol or propylene glycol, or a mixture thereof. In
another embodiment the plasticizer is selected from TEC or propylene
glycol, or a mixture thereof.

[0069]Another embodiment of the invention is a co-blend of HPMC-AS, HPC
and a second swellable solid, such as HPMC. HPMC suitably is present in
this co-blend in an amount of about 2 to about 10% w/w.

[0070]In another embodiment of the invention there is a co-blend of
HPMC-AS, HMPCP, and a second swellable solid, HPMC. The HPMCP suitably is
present in this co-blend in an amount of about 15 to about 30% w/w. HPMC
suitably is present in this co-blend in an amount of about 2 to about 10%
w/w.

[0071]In another embodiment of the invention there is a co-blend of
HPMC-AS, and HPC, suitably HPC-SSL. The amount of HPC-SSL in the blend is
present from about 3 to about 25% w/w.

[0072]In another embodiment of the invention there is a co-blend of
HPMC-AS, and HPC-SSL, and a second swellable solid, HPMCP. HPMCP suitably
is present in this co-blend in an amount of about 15 to about 30% w/w,
and the amount of HPC-SSL in the blend is from about 3 to about 20% w/w.

[0073]In another embodiment of the invention there is a co-blend of
HPMC-AS, and HPC-SSL, a second swellable solid, HPMCP, and a third
swellable solid HPMC, such as Pharmacoat 603. In this blend, the HPMC-AS
is present from about 45 to about 60% w/w; the HPMCP is present in this
co-blend in an amount of about 15 to about 20% w/w, the amount of HPC-SSL
in present in the blend from about 1 to about 20% w/w, suitably about 3%
w/w to less than 20% w/w, and alternatively form about 1 to about 5% w/w;
and the HPMC is present in the blend from about 3 to about 5% w/w.

[0074]Hydroxypropyl cellulose is suitably added to the blend to help
processing and injection moulding of the shells, to give better tensile
properties, and assist in dissolution of the shell matrix in a pH
independent manner.

[0075]Addition of an HPC such as Klucel EF, has been shown to result in
moulded shells but which have longer dissolution times in high pH media
due to the swelling nature and relatively low solubility rate of Klucel,
e.g. swelling versus erosion.

[0076]Addition of a lower molecular weight HPC, such as HPC-SSL has been
shown to increase dissolution rates at higher pH, and increases
flexibility of shells to enable clipping after storage. If the level of
HPC-SSL is increased too much, the polymer matrix became too soluble in
acidic pH and the shells may fail in enteric testing, therefore, suitably
inclusion of HPC-SSL in present in the formulations in amounts of 1% to
about 25%, suitably, less than 20%.

[0077]Additionally, the presence of small amounts of HPC-SSL (1-5% w/w)
has also found to help stabilise HPMC-P in the preferred formulation
compared to formulations without this addition.

[0078]Addition of HPMC, such as Pharmacoat 603 appears to help improve
extrusion of the formulations. However, certain components containing
Pharmacoat 603 have been shown over time to become brittle. It has been
found that using HPMC in place of HPC-SSL in the formulations slows down
the dissolution rate. Samples with addition of 3% w/w SSL release between
24-36 minutes at high pH, and this is increased to 36-72 minutes when the
SSL is replaced with 5% w/w HPMC.

[0079]Shells comprising of all HPMC-AS as the enteric polymer with
complete removal of the phthalate, to help improve stability have been
tested under USP 3 conditions. The dissolution times have been shown to
be more variable and tend to be longer, although the shells behaved very
similar under USP 2 conditions. Consequently, while the all HPMC-AS
shells can be extruded and moulded, it is preferred that a co-blended of
polymers be used for enteric shells having better tensile properties.

[0080]Other suitable dissolution modifying excipients include, but are not
limited to the class of wicking agents such as the low molecular weight
solutes, such as starch, or the non-reducing sugars, such as xylitol, or
mannitol, present in the range of about 2.5 to about 15% w/w. Also
included herein are the class of water soluble fillers, such as lactose,
lactitol, maltitol, sorbitol or alternatively organic acids such as malic
acid, citric acid or succinic acid, suitably present in the range of
about 2.5 to about 15% w/w, alternatively from about 5 to about 10% w/w.
In another embodiment of the present invention the water soluble fillers
may be present from an amount of about 5 to about 20% w/w.

[0081]It is recognized that the polymeric compositions are first melted in
a melt extrusion process, and may also contain additional additives or
excipients to assist in melt flow, strength, brittleness, flexibility,
elasticity, and other moulding characteristics, these additional
excipients include but are not limited to, plasticizers, absorption
enhancers, surfactants, flavouring agents, dyes, absorption enhancers,
lubricants, additional dissolution modifying agents, processing aids,
colouring agents, flavouring agents and sweetening agents, etc.

[0082]Incorporation of a surfactant into the formulation may optionally be
desired to lower the viscosity and surface tension of the formulation.
The surfactant selection may be guided by HLB values but is not
necessarily a useful criterion. Higher HLB surfactants are Tween® 80
(HLB=10), Pluronic F68 (HLB=28), and SDS (HLB>40); lower HLB value
surfactants, such as Pluronic F92 and F127 may also be used. Pluronic,
made by BASF, USA has a synonym of POLOXAMER. Pluronic F68 for instance
has a molecular weight of 8,400. Pluronic F127 has a molecular weight of
12,600. Pluronics are polyoxypropylene-polyoxyethylene block copolymers.

[0084]Suitably, the formulation may optionally contain from about 1% to
about 10% w/w surfactant(s). In another embodiment the formulation
contains from about 1 to about 8% w/w surfactant(s). If SDS is added it
is suitably around 1% w/w. If Tween 80 is added it is around 2% w/w or
less, alternatively from about 0.5 to about 2% w/w.

[0085]The polymeric carriers or oligomeric surface modifiers, if
appropriately chosen, may themselves act as absorption enhancers.
Suitable absorption enhancers for use herein, include but are not limited
to, chitosan, lecithin, lectins, and Vitamin E-TPGS, and combinations or
mixtures thereof. Suitably, these absorption enhancers if present are in
a range of about 1 to about 20% w/w.

[0086]Plasticizers may be employed to assist in the melting
characteristics of the composition. A plasticizer may increase the
flexibility of the moulded parts and reduces the melt viscosity which
then aids the extrusion and injection moulding process. Various
plasticizers were found to plasticize the enteric polymers (HPMC-AS and
HPMC-P) to varying degrees, each plasticizer had its own benefits and
drawbacks on the desired critical attributes for the enteric dosage form.

[0088]Triethyl citrate is a good plasticizer of HPMC-AS and HPMC-P
providing shells with good physical properties, and an adequate
dissolution profile with few enteric failures, and a high pH release
occurring typically within 45 minutes.

[0089]It has been found that for formulations containing HPMCP, the
plasticizer TEC has shown some chemical instability, likely due to the
acidic nature of the TEC. It is believed that as HPMC-Phthalate degrades,
the phthalic acid functional group is removed from the cellulose
backbone, and this can alter the chemistry of the polymer and change its
pH response. Suitably, the presence of phthalic acid in the formulations
is limited to less than 1% of the HPMC-P polymer present for long term
stability.

[0090]In one embodiment of the present invention the plasticizer triacetin
is used in combination with the HPMC-AS co-polymer blend.

[0091]In another embodiment of the present invention the plasticizer
triethyl citrate is used in combination with the HPMC-AS co-polymer
blend.

[0092]In another embodiment of the present invention the plasticizer
glycerol is used in combination with the HPMC-AS co-polymer blend. In
another embodiment of the invention the plasticizer glycerol is used for
formulations which further comprise as a copolymer blend with HPMC-AS, an
HPMC-P component (HP-50).

[0093]In another embodiment of the present invention the plasticizer
propylene glycol is used in combination with the HPMC-AS co-polymer
blend.

[0094]Suitably, the plasticizer is present in an amount of about 1 to
about 20% w/w, suitably about 1 to about 15% w/w. In one embodiment of
the invention the plasticizers are present in an amount from about 2.5 to
about 15% w/w, in combination of mixtures thereof. In another embodiment
the plasticizer is present in an amount from about 5 to about 10% w/w.

[0095]If a single plasticizer is used, such as triacetin, suitably it will
be in an amount of about 2.5 to about 15% w/w, and 4 to 10%; and 5 to 8%.
If triethyl citrate is use, suitably it is in the range 2.5 to about 15%
w/w, and 4 to 10%; and 5 to 8%.

[0096]If the plasticizer is glycerol, suitably it will be in an amount of
about 2.5 to about 15% w/w, 5 to 13%; and 5 to 8%.

[0097]If the plasticizer is propylene glycol, suitably it will be in an
amount of about 4 to about 15% w/w, and from 4 to 10% w/w.

[0098]In another embodiment of the invention a combination of plasticizers
are used, such as propylene glycol with TEC or glycerol with propylene
glycol. The amount of plasticizers in combination may be slightly higher
than the individual component, suitably from about 1 to about 20% w/w. In
another embodiment from about 10 to about 20% w/w, more suitably together
about 15% w/w.

[0099]Replacement of propylene glycol and glycerol with polyethylene
glycol (PEG) 400 provides shells with a reasonably reproducible
dissolution profile, and a high level of enteric protection. However,
generally the moulded shells showed poorer tensile properties, and
difficulty with clipping to linkers. This could mean that PEG 400 is
simply not an effective plasticizer for one or more of the enteric
polymers present in a co-blended formulation.

[0100]It has been determined that when the polymer HPMC-AS LG is used in
combination with the plasticizer triacetin that an optimal ratio of
HPMC:triacetin is from about 4:1 to about 7: 1, preferably closer to 7:1.
In such cases the lubricant, preferably stearyl alcohol, is suitably
maintained at approximately 5-7% w/w to the total formulation with the
remainder of the formulation being the dissolution modifying
excipient/agent, and any other additives as necessary. Suitably, the DME
is a swellable solid, preferably HPC or blends of HPC. In one embodiment
the HPC polymer is Klucel EF.

[0101]The use of triacetin has demonstrated good extrusion, moulding and
overall effective plasticization with the enteric cellulosic polymers
herein. Shells with higher levels of triacetin are shown to be more
unstable on store but not an issue at the levels commonly used herein.

[0102]Additional regents, generally classified as processing aids, include
strengthening agents, such as talc. Suitably, the processing aids are
present from about 0.5 to about 10% w/w. In another embodiment, the
processing aids are present from about 0.5 to about 5% w/w.

[0103]An internal lubricant is one which can provide lubrication at the
die wall in the extrusion process, and mould wall in the injection
moulding process. Suitable mould processing lubricants, or glidants for
use herein, include but are not limited to, stearyl alcohol, stearic
acid, glycerol monostearate (GMS), talc, magnesium stearate, silicon
dioxide, amorphous silicic acid, and fumed silica; lauric acid, lecithin,
sucrose fatty acid esters such as those derived from stearic acid, oleic
acid, palmitic acid, and lauric acid; and combinations or mixtures
thereof. It is believed that the lubricant functions primarily as a flow
promoter for the composition. One embodiment of the present invention is
the use of stearyl alcohol as a suitable lubricant. Suitably, a
commercial grade of stearyl alcohol, such as Crodacol S95 (Croda
Oleochemicals) is used herein. Suitably, a commercial grade of sucrose
fatty acid esters such as those derived from stearic acid, oleic acid,
palmitic acid, and lauric acid may be obtained from Mitsubihi-Kasei Foods
as SurfHope®. The amount of lubricant present in the formulation is
from about 2% to about 10% w/w. In another embodiment the lubricant is
present from about 4% to about 8% w/w.

[0104]If stearyl alcohol is used, it is suitably present in an amount of
about 2.0 to 10% w/w. In another embodiment the stearyl alcohol is
suitably from about 4 to about 8% w/w. In another embodiment the stearyl
alcohol is suitably from about 5 to about 7% w/w. In another embodiment
the stearyl alcohol is suitably about 5 to about 6.25% w/w.

[0105]Suitably, the lubricant should act as a mould processing lubricant
and cause little mold distortion, i.e. crumpling of the multidosage
compartment shell when the hot soft shell is taken out of the mould.
Suitably, the lubricants for use herein do not introduce any metal ion
contamination.

[0106]One embodiment of the present invention is the combination of the
polymer HPMC-AS, stearyl alcohol, at least one swellable solid, and at
least one plasticizer. The swellable solid may be the polymer
hydroxypropylcellulose or a blend of hydroxypropylcellulose derivatives;
or the swellable solid may be HPMCP; or the swellable solid my be
HPC-SSL; or the swellable solid may be HPMCP and HPC; or the swellable
solid may be a blend of HPMCP and HPC-SLL; or the swellable solid may be
a blend of HPMCP, HPC-SLL and HPMC.

[0107]In one embodiment an optimal ratio of HPMC-AS: HPC is in the range
of 0.8:1. Levels of 0.5:1 may produce suitable part with reduced release
time and reliable enteric performance.

[0108]Another embodiment of the present invention is the combination of
the polymer HPMC-AS, stearyl alcohol, at least one swellable solid, and
at least two plasticizers. The combination of plasticizers are suitably
propylene glycol with TEC, or glycerol with propylene glycol.

[0109]While the compositions herein may be moulded in varying
wall-thickness, it is preferably that capsules or components have a
wall-thickness of about 0.3 to about 0.8 mm, suitably 0.4 -0.5 mm.
However, dissolution performance will more appropriately tailor the wall
thickness depending upon the release profiles desired. Increases in wall
thickness may be necessary to reduce warping of the components, or
modification of the additional excipients in addition to this may be
necessary.

[0110]The final products of this invention, i.e. the capsule shells, and
or other components and sub-units may additionally include materials in
the polymer blends of which they are made to enhance the ease with which
they can be welded together. The sub-units may additionally be provided
with constructional features and/or include materials in the polymer
materials of which they are made to enhance the ease with which they can
be joined together, either by simple mechanical joints, or welded
together. A suitable material for assisting such are opacifier materials
such as carbon (e.g. 0.2-0.5%), iron oxides, Ferric oxide (e.g.
0.2-0.5%), or titanium dioxide (e.g. 0.5-1.0%) which help the polymer.

[0111]For example each of a plurality of sub units, e.g. of the capsule
compartments, linker sub-units, or combinations thereof may comprise the
same or different polymer(s). For example each of a plurality of sub
units, e.g. of capsule compartments, linker sub-units, or combinations
thereof may comprise the same or different drug substance. For example
each sub-unit may contain the same drug substance but release the
contents into the gastro-intestinal tract of the patient at a different
rate, at different times after administration to the patient or at
different places in the patient's gastro-intestinal system. Alternatively
each sub-unit may contain a different drug substance, each of which may
be released at the same or a different rate or time after administration
or place in the patient's gastro-intestinal system.

[0112]For example two or more sub-units, e.g. two capsule compartments or
a linker may each contain different drug substances, and/or different
drug substance formulations, and/or the same drug in different
formulations, so that a combination of two or more drug substances having
different release rate profiles, or formulations thereof, may be
administered to a patient.

[0113]The dosage form of this invention enables the assembly together of
sub-units which differ in their drug content and/or drug content release
characteristics to provide a dosage form tailored to specific
administration requirements.

[0114]The dimensions and shape of each of the sub-units and hence of the
overall assembled dosage form may be determined by the nature and
quantity of the material to be contained therein and the intended mode of
administration and intended recipients. For example a dosage form
intended for oral administration may be of a shape and size similar to
that of known capsules intended for oral administration.

[0115]The dosage form is particularly suitable for presentation as an oral
dosage form containing one or more drug substances suitable for oral
administration, and appears to be suitable for all types of such drug
substance.

[0116]The drug substance(s) contained in any capsule compartment may be
present in any suitable form, e.g. as a powder, granules, compact,
microcapsules, gel, syrup or liquid provided that the capsule compartment
wall material is sufficiently inert to the liquid content of the latter
three forms. The contents of the compartments, e.g. drug substances, may
be introduced into the compartments by standard methods such as those
used conventionally for filling capsules, such as dosating pins or die
filling.

[0117]The sub-units may differ from each other in their drug content
release characteristics, and this may be achieved in various ways. For
example, one or more solid sub-units and/or capsule compartments may be
substantially immediate release, i.e. releasing their drug contents
substantially immediately upon ingestion or on reaching the stomach. This
may for example be achieved by means of the matrix polymer or the capsule
compartment wall dissolving, disintegrating or otherwise being breached
to release the drug content substantially immediately. Generally,
immediate-release sub-units are preferably provided by being capsule
compartments. The other subunit may alternatively be an immediate release
subunit which comprises an enteric coating over the subunit.

[0118]For example, one or more solid sub-units and/or capsule compartments
may be sustained-release sub-units. Preferably these are solid sub-units,
as a bulk matrix of polymer is likely to dissolve or disperse more slowly
to release its drug content that a thin walled capsule.

[0119]For example, one or more solid sub-units and/or capsule compartments
may be pulsed-release sub-units for example releasing their drug content
at a specific predetermined point in a patient's gastro-intestinal
system. This may be achieved by the use of polymer materials which
dissolve or disperse only at defined pH environments, such as the above
mentioned HPMC-AS or certain Eudragit® polymers, for instance
Eudragit E100 which is acid labile.

[0120]For example in the above-described capsule
compartment-linker-capsule compartment dosage form one capsule
compartment may be effectively immediate release and the other may be
sustained, delayed or pulsed release. To achieve this for example one
capsule compartment may be made of polymer materials which cause the
capsule compartment to release its drug content in the stomach or upper
part of the digestive tract, and the linker (acting as a closure for the
second compartment) and the second compartment itself may be made of
materials e.g. the above described enteric polymers, which release their
drug content only in the intestinal environment.

[0121]Determination of the time or location within the gastro-intestinal
tract at which a sub-unit releases its drug substance content may be
achieved by for example the nature of the sub-unit material, e.g. a solid
sub-unit matrix polymer or a capsule compartment wall material, or in the
case of an end compartment which is closed by a closure, by the nature of
the closure material. For example the wall of different, e.g. adjacent,
compartments may be made of polymers which are different or which
otherwise differ in their dissolution or disintegration characteristics
so as to endow different compartments with different drug release
characteristics. Similarly for example the polymer matrix material of
different, e.g. adjacent, solid sub-units may be made of polymers which
are different or which otherwise differ in their dissolution or
disintegration characteristics so as to endow different solid sub-units
with different drug release characteristics.

[0122]For example the matrix, wall or closure material may be a polymer
which dissolves or disperses at stomach pH to release the drug substance
in the stomach. Alternatively the wall material of different compartments
may differ so that different compartments have different release
characteristics.

[0123]For example a linker or closure sub-unit or a capsule compartment
may have respectively a matrix or a wall or a closure comprising an
enteric polymer which dissolves or disperses at the pH of the small or
large intestine to release the drug substance in the intestine. Suitable
such polymers have been described above, for example, with reference to
U.S. Pat. No. 5,705,189.

[0124]Additionally or alternatively the wall material may differ in
thickness between compartments so that thicker walled compartments
disrupt more slowly than thinner walled compartments.

[0125]Additionally or alternatively the compartment walls or the closure
may have areas or points of weakness which preferentially dissolve and
may thereby determine the time of onset and/or rate of release of the
drug substance content. For example such points of weakness may comprise
holes, e.g. small holes, e.g. laser-drilled holes in the compartment wall
or the closure, these holes being closed and/or covered with a film of a
polymer material that dissolves at a pre-determined point in the
digestive tract, for example an enteric polymer material. For example
such points of weakness may comprise thinned parts in a capsule
compartment wall formed during the molding operation in which the capsule
compartment is formed.

[0126]The sub-units may additionally or alternatively have surface or
other constructional features that modify their drug release
characteristics. For example solid sub-units may be provided with
internal cavities or channels to create a large surface area. For example
solid sub-units may be in the form of hollow cylinders, donuts, or
toroids, which shapes are known to tend towards first-order dissolution
or erosion in liquid media and correspondingly to tend toward first-order
release of drug content dispersed therein.

[0127]"Pharmaceutically acceptable agents" includes, but is not limited
to, drugs, proteins, peptides, nucleic acids, nutritional agents, as
described herein. This term includes therapeutic active agents, bioactive
agents, active agents, therapeutic agents, therapeutic proteins,
diagnostic agents, or drug(s) as defined herein, and follows the
guidelines from the European Union Guide to Good Manufacturing Practice.
Such substances are intended to furnish pharmacological activity or other
direct effect in the diagnosis, cure, mitigation, treatment, or
prevention of a disease or to affect the structure and function of the
body. The substance may also include a diagnostic agent, such as an
imaging agent and/or a radioactive labeled compound. Their use may be in
a mammal, or may be in a human. The pharmacological activity may be
prophylactic, or for treatment of a disease state. The agents herein
include small molecule therapeutics, as well as peptides and proteins.
The pharmaceutical compositions described herein may optionally comprise
one or more pharmaceutically acceptable active agent, bioactive agent,
active agent, therapeutic agent, therapeutic protein, diagnostic agent,
or drug(s) or ingredients distributed within.

[0128]As used herein the term's "active agent", "drug moiety" or "drug"
are all used interchangeably.

[0129]The terms "mold" and "mould" are used interchangeably herein.

[0130]Water solubility of an active agent is defined by the United States
Pharmacoepia. Therefore, active agents which meet the criteria of very
soluble, freely soluble, soluble and sparingly soluble as defined therein
are encompassed this invention.

[0132]Preferred drug substances include those intended for oral
administration and intravenous administration. A description of these
classes of drugs and a listing of species within each class can be found
in Martindale, The Extra Pharmacopoeia, Twenty-ninth Edition, The
Pharmaceutical Press, London, 1989, the disclosure of which is hereby
incorporated herein by reference in its entirety. The drug substances are
commercially available and/or can be prepared by techniques known in the
art.

[0133]The polymeric blends can be preferably selected from known
pharmaceutical polymers. The physico-chemical characteristics of these
polymers, as well as the thickness of the ultimate injection molded
component, will dictate the design of the dosage form, such as rapid
dissolve, immediate release, delayed release, modified release such as
sustained release, controlled release, or pulsatile release, etc.

[0134]The polymer blends are made by well-known methods for producing hot
melt extrusions in which the selected ingredients are fed into a feed
hopper of an extrusion machine. Suitable well known equipment is readily
available for producing a hot melt extrusion of the blends herein.

[0135]The present invention is directed to a formulation that once moulded
into a suitable capsule shell and/or linker does not require a film
coating for acidic protection. Suitably, the desired subunit, e.g. a
capsule shell, linker, endcap, etc. can be assembled by mechanical fit,
and can readily be combined with another enteric shells or with another
shell formulations to give a range of release profiles in a single unit.
Suitable formulation are chosen on the basis of acceptable performance in
a number of factors, such as but not limited to:

[0136]1. Suitability for extrusion;

[0137]2. Ability to be injection moulded in a variety of subunits or
components;

[0138]3. Physically stable (no warping, shrinking, cracking, etc.);

[0139]4. Chemically stable with respect to the polymers present;

[0140]5. Able to assembled manually/automatically (clipped) to a linker or
solid matrix subunit;

[0141]6. Survive at least 2 hours in acid media with no release taking
place; and

[0142]7. Dissolve/release at a pH above 6 in less than 45 minutes

[0143]Another aspect of this invention therefore, is a multicomponent
dosage form which contains a capsule shell produced in accordance with
the formulations described herein, and a suitable linker formulation,
which can be easily assembled, such as by mechanical force, e.g.
clipping, or by welding if desired, and which dosage form does not
require any additional manipulation, such as external coating to provide
an enteric release profile. Such multicomponent dosage form could be
further extended to include an immediate release or a second pulsatile
capsule or linker component as desired.

[0144]Therefore, one aspect of the invention is a multicomponent dosage
form comprising a plurality of sub-units, and wherein each sub-unit being
selected from

[0145](a) at least one shell including a first wall portion at least
partially defining an interior space configured to hold a drug substance,
the first wall portion being configured to dissolve within a
gastrointestinal environment; and

[0146](b) at least one linker including a second wall portion having a
substantially cylindrical outer surface, the second wall portion
configured to dissolve within a gastrointestinal environment;

[0147]and wherein the drug substance containing capsule has a shell wall
comprising hydroxypropylmethylcellulose acetate succinate (HPMC-AS)
present in an amount of about 10 to 70% w/w, a plasticizer present in an
amount of about 1% to about 20% w/w, a lubricant present in an amount of
about 2% to about 15% w/w, and a swellable solid present in an amount of
about 10 to about 60% w/w, and containing a drug substance; which, at
least prior to administration to a patient, is mechanically welded or
mechanically joined into an assembled dosage form.

[0148]A suitable linker or connecting sub-unit for use in the
multicomponent dosage form is composed of ethylcellulose, stearyl
alcohol, glycerol, and BHT (butylated hydroxytoluene).

[0149]Another suitable linker or connecting sub-unit for use in the
multicomponent dosage form is composed of Eudragit RL 100, HPC, and
Stearyl alcohol.

[0150]Suitably, at least one of the capsule components in the
multicomponent dosage form is of substantially sustained release, and any
second capsule shell in the multicomponent dosage form may or may not be
a formulation of the present invention.

[0151]Suitably, at least one of the multicomponent dosage form according
to any of the preceding claims which further comprises a second drug
substance-containing capsule compartment which is a substantially
immediate release.

EXAMPLES

[0152]The invention will now be described by reference to the following
examples, which are merely illustrative and are not to be construed as a
limitation of the scope of the present invention. All temperatures are
given in degrees centigrade; all solvents are highest available purity
unless otherwise indicated.

Table 1 provides a summary of formulations made and tested containing
HPMC-AS.

[0153]Additional formulations of stearyl alcohol and HPMC-AS :triacetin
have been formulated and have been shown to provide physical stability at
40/75° C. Using an HPMC-AS:triacetin ratio of 7:1, the following
HPMC-AS (LG) shell formulations have completed 1 month on storage at
30/65° C. and 40/75° C., and have been shown to be
physically stable with minimum colour change.

[0155]The following additional tables, Tables 5 to 10 demonstrate
representative compositions of the instant invention which may be
suitably extruded and moulded into dosage form components as described
herein. The formulations are all expressed in w/w % amounts. All
formulations have been extruded and injection moulded into capsule shells
using the general hot melt extrusion and injection moulding methods
discussed below.

[0156]Prior to hot melt extrusion, the powder excipients of the above
noted formulations, (HPMC AS, stearyl alcohol and dissolution modifying
polymer) were blended via a bin blender. The extrusion was generically
performed on a Prism 16 mm co-rotating twin-screw extruder with a
temperature profile range from die to feed throat of
120-120-115-110-90-20° C. and screw speed of 200 rpm. It is
possible that the temperature range for the above examples may have
varied by 10° C. +/-. The extruder was fed by a gravimetric powder
feeder and the triacetin which is a liquid was added via a Gilston
Minipuls 2 peristaltic pump, total combined feed rate was set to equal
approximately 1.0 kg/hr. The formulations were extruded through a 3 mm
die to produce a strand that was then air cooled and then palletized.

Injection Moulding

[0157]The pellets produced from the hot-melt extrusion process above were
injection moulded using an MCP 12/90 HSP mini moulder into prototype 9.0
mm diameter×6.9 mm height capsule shell, with a wall thickness of
0.5 mm; or a 7.7 mm diameter×9 mm height capsule shell. Typically
the screw, plunger and barrel temperature was set to 120-140° C.
and a probe temperature to 170 to about 190° C. as the upper
temperature.

[0158]It has been found that dissolution testing, either for enteric
protection or for release alone is not a good predictor of a formulations
acceptance in many cases. A number of formulations provide similar
release profiles and additional investigations into stability or tensile
strength may be necessary.

[0159]Enteric shells may be tested using at least three known methods of
dissolution tests, a USP II paddle method to simulate the standard USP
enteric protection test using a pH switch method to coincide with testing
typically performed for enteric dosage forms; a USP III test, which may
be more bio-relevant, using a set agitation rate of 10 dips per minute
(DPM); and a 2 hour enteric challenge, as this test is more relevant to
in vivo performance (as no sinkers are used and the dosage form can float
and sink).

[0160]The USP III is also used to determine the maximum amount of time a
formulation could withstand an acidic environment before releasing. This
test does make an assumption that not all units would exit the stomach in
a rapid manner and could be retained for extended periods of time (in the
stomach) before getting to a high pH intestinal region. Therefore this
test is performed by holding the unit in the low pH phase for at least 6
hours and checking for release.

USP II Methodology

[0161]The injection moulded shells are dosed with paracetamol, as a marker
drug, and sealed by clipping to an 8.35 mm diameter, 3.80 mm height
injection moulded linker unit. Dissolution analysis is performed via the
USP2 paddle method at 100 revolutions per minute, with 2 hours in pH 1.6
0. IN hydrochloric acid followed by 2 hours in pH 6.8 phosphate buffer
with 0.06% sodium dodecyl sulphate, and units were placed in the vessels
in Japanese cage sinkers.

USP III Methodology

[0162]The injection moulded shells are dosed with metformin, as a marker
drug, and sealed by clipping to an 8.35 mm diameter, 3.80 mm height
injection moulded linker unit. Dissolution analysis is performed via USP3
method at 10 dips per minute, with 2 hours in pH 1.2 simulated gastric
fluid followed by 6 hours in pH 6.8 simulated intestinal fluid with the
units placed in the baskets without sinkers.

[0163]The methods above use either pH 1.2 SGF or pH 1.6 0.1 N HCl as the
acidic phase, and either pH 6.8 SIF or pH 6.8 phosphate buffer. These
mediums are essentially interchangeable so long as the pH is kept low in
the acidic phase (ideally <2) and the high pH phase is above the pH
dissolution threshold for the enteric polymers present which in most
cases is above pH 5.5.

USP II/III of Final IR/ER Formulations

[0164]To confirm completed units with different formulated shells can
provide variable release profiles from a single dosage form, shells are
tested with an immediate release shells of the same dimensions. FIG. 6
demonstrates a typical USP II plot showing complete units comprising of
IR and enteric shells.

[0165]Injection moulded shells which were dosed with Metformin, used as a
marker drug, were sealed by clipping to an 8.35 mm diameter, 3.80 mm
height injection molded linker unit unless otherwise indicated.
Dissolution analysis was performed via USP3 method at 10 dips per minute,
with 2 hours in pH 1.2 simulated gastric fluid followed by 6 hours in pH
6.8 simulated intestinal fluid with the units placed in the baskets
without sinkers.

[0167]Extrusion of this linker component was performed using a 16 mm
twin-screw extruder at temperatures ranging between 120-130 degrees
° C. and samples were moulded to form linker shaped components at
temperatures between 160-180° C.

[0170]Using a higher molecular weight grade of HPMC-AS HG (dissolves at
6.5-7.0), in combination with two levels of the plasticizer triacetin and
the lubricant stearyl alcohol, two formulations have been made and
tested.

[0171]Similar formulations using HPMC-AS LG (pH 5.5) and MG (pH 5-5.6)
with 5% w/w levels of triacetin have also been made.

[0172]Linkers were also produced from the HPMC-AS HG polymer using two
alternative plasticizers, glycerol and triethyl citrate. In both cases,
the alternative plasticizer was added at a 5% w/w level. Stearyl alcohol
was present in both cases at the 5% w/w level. It was noted that the
maximal extruder torque for the glycerol formulation was exceeded and the
glycerol level had to be increased to 10% w/w to match the torque
produced by the triacetin plasticized formulation, suggesting that
glycerol was a less effective plasticizer than triacetin for this
composition. In contrast, the triethyl citrate formulation ran at a
similar torque to the comparative triacetin formulation.

[0173]The extrusion of linker blends was performed on a Prism 16 mm
co-rotating twin-screw extruder with a temperature profile from die to
feed throat of 120-120-115-110-90-20° C. and screw speed of 200
rpm. The extruder was fed by a gravimetric powder feeder and the
triacetin which is a liquid was added via a Gilston Minipuls 2
peristaltic pump, total combined feed rate was set to equal approximately
1.0 kg/hr. The formulations were extruded through a 3 mm die to produce a
strand that was then air cooled and then palletized.

Results

[0174]Generally the formulations could be extruded and formed strands that
were suitable for pelletisation. The level of plasticizers in the
formulation assists in determining the overall flexibility of the shells.
It is recognized that some of the formulations described while mouldable,
may produce parts which have characteristics that made them unsuitable
for commercialization, e.g. they produce parts that are too brittle to
clip, are prone to frequent cracking, and/or have excessive stretching.

[0175]A lubricant is deemed is deemed necessary for formulations herein as
removal of the lubricant, e.g. stearyl alcohol, produces parts that stick
in the mould cavities. Stearyl alcohol was removed completely from
Formulation 5, Table 1 to assess whether the triacetin could be used
alone to lower the melt viscosity for injection moulding and extrusion.
Complete parts could not be formed from this formulation, suggesting an
inadequate amount of plasticizer. In formulation 11, Table 1, the level
of plasticizer was increased, and this produced shells that stuck in the
mould cavities. The removed shells were complete and very flexible but
were deemed inelastic and did not return to their shape upon deformation
suggesting the shells were over-plasticized.

[0176]A suitable plasticizer level is required to produce parts which have
flexibility, such as for attachment to a linker, which produce stable
components, and which are dimensionally correct. This is exemplified
herein with observations of formulations 3 and 4 in Table 1.

[0177]Dissolution analysis of the unit from Formulations 3 and 4, Table 1
showed gastric resistance for 2 hours and release in simulated intestinal
fluid. Formulation 4 produced variable dissolution profiles; which
variability was reduced in Formulation 3. The addition of HPC
(Formulation 6, Table 1) to the formulation allowed the units to
partially hydrate in the gastric fluid. This reduces the time to release
in the intestinal fluid while still providing gastric resistance.
Dissolution analysis with 8 hours in gastric fluid showed that after
extended gastric residence the units although hydrated, continue to
maintain gastric resistance. This formulation was repeated with the
HPMC-AS grade substituted for MG and HG. The different grades
demonstrated extend the time to release in the intestinal fluid. FIG. 1
demonstrates a dissolution profile of a 60% HPMC-AS (LG)/20% Klucel
EF/10% Triacetin/10% stearyl alcohol shell (a 60:20:10:10 formulation) in
simulated gastric fluid.

[0178]These formulations survive exposure to SGF fluids for about 2 hours,
and then release within 1 hour of exposure to SIF. For the most part,
linkers used with capsule shell components of this invention are desired
to be insoluble under gastric conditions, thus providing a dosage form
which releases as a pulsatile release dosage form in the small
intestines.

[0179]Additional USP 3 release times for representative formulations of
the invention are shown below. These release times, are a `typical`
release for each formulation. Only USP 3 data is shown at the same run
conditions, and using the same size/wall section shells and the same
linkers, in this instance a RL100 linker composition, for all units to
provide comparison of the formulations.

[0180]The results described herein do not provide a full and conclusive
set for all formulations made, and are only a representative release time
for comparative purposes. The table below is one such representative
sample:

[0181]A number of different linker variants (e.g. RL100, ethylcellulose,
and HPMC-AS) have been tried with the formulations of the present
invention. The RL 100 linkers have demonstrated a tendency to swell and
hydrate over longer periods of time. While this may not be an issue with
formulations suitable for immediate release it is possible that this
might be an issue with the enteric units retained in the stomach for long
periods of time as release could occur through the linker rather than
through the shell dissolution.

[0182]Previously moulded HPMC-AS linkers have generally been found to be
smaller than RL100 linkers, and do not swell as well resulting in linkers
which fall out of the shells before they have time to fully dissolve,
often ending in enteric failures. HPMC-AS and ethylcellulose linkers
however, can be used with formulations containing HPC such as those with
Klucel EF at around 20% w/w as these formulations have been found to
hydrate and swell in acidic media, and therefore hold the linker into the
shell to prevent premature release. This can turn a formulation with a
previously long lag in release to a much quicker and more reproducible
release.

[0183]The dissolution profile of enteric shells containing Klucel EF,
which is known to swell, will slow down the release rate when used with
RL100 linkers. In contrast, using ethyl cellulose linkers the release is
much faster and more consistent, going from 60-120 minutes with an RL100
linker to 44-68 minutes with an ethyl cellulose linker as can be seen in
FIG. 2 herein.

[0184]The above description fully discloses the invention including
preferred embodiments thereof. Modifications and improvements of the
embodiments specifically disclosed herein are within the scope of the
following claims. Without further elaboration, it is believed that one
skilled in the area can, using the preceding description, utilize the
present invention to its fullest extent. Therefore, the Examples herein
are to be construed as merely illustrative and not a limitation of the
scope of the present invention in any way. The embodiments of the
invention in which an exclusive property or privilege is claimed are
defined as follows.